The overall goals of this Program Project are to advance cure rates in acute lymphoid and myeloid leukemias and to improve understanding of these diseases at the cellular and molecular levels, in ways that may have clinical application. These broad objectives will be achieved through a coordinated series of five research projects, incorporating both therapeutic and laboratory studies, with support from administrative, biostatistical, and laboratory central shared resources (CORE). In Project 1, the thrust will be to improve event-free survival in patients with acute lymphoblastic leukemia (ALL) by more carefully targeting chemotherapy to achieve optimal systemic exposure of leukemic cells effective agents. This aim will be expanded in a subsequent trial by using recombinant hematopoietic growth factors to attenuate dose-limiting myelosuppression, thereby permitting higher systemic exposure to antileukemic drugs. Studies on the cell biology of ALL will stress careful, uniform determinations of immunophenotype, karyotype, DNA index, and molecular abnormalities in leukemic lymphoblasts, with rigorous determination of clonality in cases with apparent phenotypic and karyotypic changes at relapse. Individualization of drug dosing by pharmacodynamic models will be extended to patients with acute myeloid leukemia (AML) in Project 2; this trial will be followed by efforts to extend remission durations by use of autologous bone marrow transplantation, with IL-2 augmentation to stimulate antileukemic activity through both cell-mediated and humoral cytotoxic effector mechanisms. Pivotal to Projects 1 and 2 are studies in Project 3 to define relationships between the disposition of anticancer drugs and their clinical pharmacologic effects (pharmacodynamics); results generated by this project will be readily exportable to clinical trials. Myeloid cell biology will be studied in Projects 4 and 5, with emphasis on the role of genes encoding CSF-I and its receptor in AML (Project 4), growth factor requirements for proliferation of leukemic myeloblasts, and characterization of aberrant differentiation by leukemic blasts maintained in vitro (Project 5). Investigators in the latter project will also assess the role of myeloid transforming genes in the regulation of blast cell growth and differentiation. An important advantage of the Program Project is the ability to provide well-characterized leukemic cell samples from each patient to all laboratory investigators. This planned 5-year program, integrating cell biology and clinical studies, should contribute significantly to the rapidly accelerating progress in acute leukemia research.